A major emphasis of this project has been the use of the SIV/macaque model of AIDS for the evaluation of potential vaccine strategies. Special attention was given to a vaccine strategy that employed an attenuated vaccinia virus (modified vaccinia virus Ankara; MVA) recombinant expressing the SIVsmH4 gag-pol and env (MVA-SIV). This recombinant vector was compared to a similar recombinant that was constructed on a Wyeth vaccinia virus background (Wyeth-SIV). The Wyeth strain of vaccinia virus is not attenuated; it was used extensively in the US for immunization against smallpox. Four rhesus macaques per immunogen were immunized four times over a 46 week period. Whereas, MVA-SIV boosted antibody responses following sequential boosts, the Wyeth-SIV recombinant only boosted at the second immunization and antibody levels declined subsequently. Following four sequential vaccinia recombinant vector immunizations we attempted to boost SIV antibody responses with psoralen-inactivated SIV administered without adjuvant. Although immunization did not prevent infection following intravenous challenge with uncloned SIVsm, the dynamics of virus replication were altered significantly. Two of the MVA-SIV-vaccinees exhibited sustained control of viremia throughout 2.5 years following challenge. This pattern of viremia was associated with maintenance of normal lymphocyte subsets and disease-free status, analogous to long term nonprogressors of HIV-1 infection. An additional MVA-SIV vaccinee exhibited controlled viremia for the first year and subsequently virus load increased concurrent with declining CD4 lymphocyte numbers; this animal still remains healthy at 2.5 years. In contrast, all four of the Wyeth-SIV vaccinees and three of the naive control group developed AIDS by 2.5 years. These observations suggest that immunization with MVA-SIV significantly modified the subsequent pathogenesis of SIV infection. A combinatorial phage library of the antibody repertoire in a lymph node biopsy of a 7 year, healthy survivor of SIV-infection was used to generate four SIV envelope-specific Fab clones; two are capable of neutralizing SIV in vitro with high efficiency.